Gene therapy as a treatment for cancer has advanced from the theoretical to the possible: in a pilot study published in August in the journal Science, investigators reported that two of 17 patients with advanced melanoma responded to a treatment known as genetically engineered therapy.
Genetically engineered gene therapy uses autologous T-cells that are extracted and cultured and treated with cytokines. Therefore, when they are reimplanted, they can activate the immune system.
In a study led by Steven A. Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute in Bethesda, Md., investigators harvested one patient’s T-cells and genetically isolated the T-cell receptor so that it would be specific to melanoma. They then removed T-cells from 17 melanoma patients and genetically spliced in the one patient’s tumor-specific receptors. Finally, they cultured those cells and transfused them into the patients. Among these patients, the investigators documented “dramatic and durable regression” of the tumors in two patients.
This study is one of several steps in a long process to develop immunotherapy approaches for the treatment of metastatic melanoma, said Dr. Rosenberg in a phone interview. “We have studied immunotherapy for the treatment of metastatic melanoma, and we have reported on cell transfer therapies that represent the most effective treatment for metastatic melanoma.”
Genetically engineered gene therapy may offer promise for refractory cases, he said. “If otolaryngologists have patients with metastatic melanoma, and it’s refractory to standard treatments, we may have something for them,” he said. “The ongoing clinical trials are continuing to show the promise reflected in the recently published trial. If a physician has patients with refractory metastatic melanoma, he or she should consider referring such patients for one of these newer cell transfer therapies.”
An Important First Step
Two gene therapy experts who were not involved in the study stressed that the findings are exciting despite the fact that only two patients had responded at the time of publication.
“The exciting thing about the current research is that the investigators took cells from the blood and made them cancer-specific,” said Andrew G. Sikora, MD, PhD, in a phone interview. Dr. Sikora, who was not involved in the current research, is a clinical fellow in Head and Neck Surgery at the M. D. Anderson Cancer Center in Houston. “It’s one of the first studies utilizing gene therapy in which patients have had a positive response to treatment.” Dr. Sikora, who is currently doing cancer immunology research with the department of Melanoma Medical Oncology, also pointed out that the investigators in the current study treated patients with the most advanced disease states. “If the approach is validated in patients with serious, advanced melanoma, it may be that patients who have less advanced disease have a better chance of responding to it,” he said.
“This is one of the first studies in humans to show an effective treatment for cancer with adoptive gene therapy,” said Bert W. O’Malley, Jr., MD, in a phone interview. “Although only two patients responded, the key is that patients did respond. Two of 17 are over 10 percent, which is remarkable considering the deadly nature of melanoma.” Dr. O’Malley, who was not involved in the study, is the Gabriel Tucker Professor and Chair of the Department of Otorhinolaryngology–Head and Neck Surgery at the University of Pennsylvania Health Systems in Philadelphia, where he is the co-director of both the Center for Head and Neck Cancer and the Center for Cranial Based Surgery.
“Gene immunotherapy had not left preclinical studies in head and neck,” he said, noting that it was somewhat understandable that a breakthrough would occur in melanoma. “Melanomas tend to be immune-responsive, unlike squamous cell carcinomas. We still have no data to show whether this approach would be effective in squamous cell carcinoma, or in salivary or thyroid tumors, the most common cancers that we treat.”
Another gene therapy strategy, adoptive gene therapy, uses autologous tumor-infiltrating lymphocytes (TILs). Although this approach is associated with up to a 50% objective response rate, not all patients have harvestable TILs, Dr. Sikora said.
“The unique factor of this study is its novel approach: to take T-cells from the patient’s blood and increase the number of tumor-specific T-cells before injecting them back into the patient,” he said. “It’s a way to help patients whose TILs can’t be harvested, and it’s one of the first cases of using gene therapy against cancer that’s been successful. It’s an important proof-of-principle study.”
Potential to Complement other Approaches
The approach could be used to complement other gene therapy or immunotherapy approaches, Dr. Sikora said. For example, it could be used in combination with vaccine therapy or with a stronger lymphodepletion regimen. Lymphodepletion uses chemotherapy, radiation, or a combination to reduce the number of nonspecific T-cells so that the body’s capacity for cancer-specific T-cells is increased. Adding radiation to the lymphodepletion regimen would be another way to modify the technique to make it more effective, he said.
Dr. Sikora’s and his colleagues’ research is investigating translational work that uses a mouse model of adoptive immunotherapy and vaccination that is similar in many respects to adoptive cell therapy in human trials, and they also are involved in melanoma immunotherapy clinical trials.
The research involving gene therapy as a way to address melanoma should interest head and neck surgeons, Dr. Sikora said. “This approach may one day improve outcomes in patients with metastatic disease or regional disease at high risk of metastasis,” he said. “It’s just as relevant to head and neck melanoma as it is to melanoma at any other site of the body. We should be involved in this and other gene therapy techniques.”
He added that the approach was applicable to other malignancies that head and neck surgeons address. For example, head and neck surgeons are very interested in squamous cell carcinoma, the most common cancer that they treat. “Some immunotherapy research is applicable to squamous cell carcinoma, particularly research involving the genes NY-eso-1 and p53, antigens that are involved in squamous cell carcinoma,” he said.
Head and neck surgeons should take heart from the findings, Dr. O’Malley agreed. “This study should be a source of stimulation for researchers to continue the work in areas other than melanoma,” he said. “Our cancers are difficult to treat, and this is a fantastic development that allows us to think through this whole concept of gene therapy. This work is an example of persistence paying off.”
©2006 The Triological Society